Methods for producing nateglinide B-type crystals

ABSTRACT

A method for producing B-type crystals of nateglinide substantially free of H-type crystals is provided, which comprises drying solvated wet crystals of nateglinide at a low temperature until no solvent remains and making a crystal conversion thereof. According to this method, B-type crystals of nateglinide can be produced at an industrial scale without allowing other forms of the crystalline polymorphism to coexist.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to methods for producingnateglinide (its chemical name:N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine) that is usefulas a therapeutic agent for diabetes. More specifically, it relates tomethods for producing nateglinide B-type crystals substantially free ofH-type crystals.

[0002] It is known that nateglinide is useful as a therapeutic agent fordiabetes because it effectively lowers blood glucose by oraladministration (Japanese Patent Publication No. Hei 4-15221). In thisconnection, the crystallization has to be carefully conducted underprecisely controlled conditions in order to separate H-type crystals anddifficulty of such crystallization procedure was problematic (seeJapanese Patent No. 2,508,949).

[0003] On the other hand, one of crystal polymorphs of nateglinide,B-type crystals, has an advantage in that the B-type crystals can beeasily prepared by conducting the crystallization under cooling.However, there is a possibility in that the B-type crystals aretransferred to the H-type crystals during the production stage. In fact,when nateglinide was prepared in industrial scale, it was found thatH-type crystals were contaminated in the resulting B-type crystals.Regarding nateglinide to be used as a medicine, it is preferable that acontamination of crystal polymorphs be as small as possible. Since thesingle crystalline form is the best desired, a method for producingB-type crystals of nateglinide by which a pharmaceutical formulationcontaining the B-type crystal exclusively without allowing other formsof the crystalline polymorphs to coexist has been desired to bedeveloped.

DISCLOSURE OF THE INVENTION

[0004] An object of the present invention is to provide methods forproducing B-type crystals of nateglinide at an industrial scale withoutallowing other forms of the crystalline polymorphism to coexist.

[0005] In the course of the study for the purpose of an efficientutilization of B-type crystals of nateglinide, the present inventorshave found that a single crystal form of nateglinide can be produced atan industrial scale by selecting the conditions of the manufacturingprocess of nateglinide, and thus the present invention has beencompleted on the basis of this finding.

[0006] That is, the present invention provides a method for producingB-type crystals of nateglinide substantially free of H-type crystals,which comprises drying solvated wet crystals of nateglinide at a lowtemperature until no solvent remains and making a crystal conversionthereof.

[0007] Preferably, the present invention provides a method for producingB-type crystals of nateglinide substantially free of H-type crystals,which comprises drying solvated materials containing nateglinidehydrates obtained by crystallizing out from a nateglinide-containingsolution under cooling, at a temperature of 50° C. or lower until nosolvent remains, and heating the resultant at a temperature of 60 to110° C. to convert the crystal form of the resultant into B-typecrystal.

BEST MODE FOR CARRYING OUT THE INVENTION

[0008] Examples of the solvated wet crystals of nateglinide employed inthe present invention include solvates with an alcohol such as methanol,ethanol and isopropyl alcohol, an acetate such as methyl acetate andethyl acetate, or water. The solvates with an alcohol or hydrate areusually used as the solvated wet crystals of nateglinide. In cases ofthe solvates with ethanol, for example, nateglinide is added to 60%ethanol aqueous solution so that the concentration of nateglinidebecomes 5 wt %, dissolved at a temperature of around 30° C. and cooleddown to 10° C. or lower to obtain the solvates.

[0009] Among these, it is preferable that the hydrates can be easilyobtained by adding water to an alcohol solution, preferably ethanolsolution, of nateglinide, cooling it to 10° C. or lower, therebycrystals are precipitated out, and separating the resulting crystalstherefrom.

[0010] Solvated wet crystals obtained are dried until no solvent remainsany longer. In this step, the temperature employed may vary depending onthe type and the amount of a solvent associated with the crystals, andmay usually be 60° C. or lower, preferably 50° C. or lower. While nolower limit of the temperature is specified, a temperature of 20° C. orhigher is usually employed in an economical point of view. Usually, itis preferable that the drying be conducted under the reduced pressure,and the drying can be completed in a short time of period when thepressure is as reduced as industrially possible.

[0011] While the drying at a low temperature can be continued untilsubstantially no solvent remains any longer, no complete absence of thesolvent is required, and the solvent may be present in an amount ofabout 5% by weight since it will be lost also upon the crystalconversion.

[0012] The dried crystals obtained are converted into B-type crystals byheating at 60 to 110° C., preferably 70 to 110° C. Usually, the crystalconversion is preferably conducted for 0.5 to 48 hours, more preferably1 to 24 hours.

[0013] H-type crystals contaminated in the B-type crystals can beanalyzed with DSC. It is preferable that no H-type crystals be detectedby analyzing B-type crystals of nateglinide with the DSC.

[0014] Rising of the drying temperature at an early stage causes nosubstantial problem when wet B-type crystals of nateglinide are dried ata small scale in a laboratory since the solvent after the separation ofthe crystals remains only in a small amount and the drier can rapidlyreach the maximum reduced pressure. However, the B-type crystals free ofH-type crystals can be produced according to methods of the presentinvention, even in a production at an industrial scale, for example,production of 5 Kg or more of the B-type crystals per one batch, inwhich the solvent remains in the crystals in a large amount after theseparation from the liquid where the crystallization is conducted andthe time period required for reaching the maximum reduced pressure isrelatively long in the drying step.

[0015] The present invention is further demonstrated with reference tothe following examples, which are not intended to restrict theinvention.

EXAMPLE 1

[0016] 24.5 kg of H-type crystals of nateglinide were added to 360 L ofethanol and dissolved by stirring at room temperature. 240 L of waterwas added thereto and cooled to 5° C. after ensuring the dissolution,and then the solution was subjected to aging at 5° C. for 1 hour. Thethus-precipitated crystals were separated to obtain 43.0 kg of wetcrystals. The crystals were dried on a rack drier at 45° C. for 24 hours(moisture content about 1 wt %) and further at 90° C. for 12 hours tomake the crystal conversion to obtain 13.3 kg of dried crystals. Thecrystals were subjected to DSC, which revealed the presence of a peakspecific to the B-type crystals (melting point: about 130° C.) withoutshowing a peak specific to the H-type crystals (melting point: about139° C.). Therefore, it is concluded that the resulting crystals areonly B-type crystals which are substantially free of the H-typecrystals.

COMPARATIVE 1

[0017] 37.0 kg of H-type crystals of nateglinide were added to 540 L ofethanol and dissolved by stirring at room temperature. 360 L of waterwas added thereto and cooled to 5° C. after ensuring the dissolution,and then the solution was subjected to aging at 5° C. for 1 hour. Thethus-precipitated crystals were separated to obtain 46.7 kg of wetcrystals. The crystals were dried with a conical drier at 30° C. for 3hours (moisture content about 10 wt %) and further at 90° C. for 12hours to make the crystal conversion to obtain 25.9 kg of driedcrystals. The crystals were subjected to DSC, which showed peaksspecific to the H-type crystals in addition to the B-type crystals.

COMPARATIVE 2

[0018] 37.0 kg of H-type crystals of nateglinide were added to 540 L ofethanol and dissolved by stirring at room temperature. 360 L of waterwas added thereto and cooled to 5° C. after ensuring the dissolution,and then the solution was subjected to aging at 5° C. for 1 hour. Thethus-precipitated crystals were separated to obtain 44.5 kg of wetcrystals. The crystals were dried with a conical drier at 30° C. for 3hours (moisture content about 10 wt %) and further at 90° C. for 15hours to make the crystal conversion to obtain 26.6 kg of dried B-typecrystals. The crystals were subjected to DSC, which showed peaksspecific to the H-type crystals in addition to the B-type crystals.

[0019] By employing the conditions according to the invention, B-typecrystals of nateglinide can be produced at an industrial scale withoutallowing other crystal forms to be present, and a pharmaceuticalformulation containing B-type crystals of nateglinide as a singlenateglinide crystal can be provided at a low cost.

What is claimed is:
 1. A method for producing B-type crystals of nateglinide substantially free of H-type crystals, which comprises drying solvated wet crystals of nateglinide at a low temperature until no solvent remains and making a crystal conversion thereof.
 2. The method of claim 1, wherein the resulting B-type crystals of nateglinide are crystals wherein H-type crystals are not detected with DSC.
 3. The method of claim 1, wherein the drying is conducted at a temperature of 50° C. or lower.
 4. The method of claim 1, wherein the drying is conducted until substantially no solvent remains any longer.
 5. The method of claim 1, wherein the solvated wet crystals are hydrates.
 6. The method of claim 1, wherein the crystal conversion is conducted by heating the solvated wet crystals at 60 to 110° C.
 7. The method of claim 1, wherein said both steps for drying said solvated wet crystal of nateglinide at a low temperature and for the crystal conversion are conducted at an industrial scale.
 8. A method for producing B-type crystals of nateglinide substantially free of H-type crystals, which comprises drying solvated materials containing nateglinide hydrates obtained by crystallizing out from a nateglinide-containing solution under cooling, at a temperature of 50° C. or lower until no solvent remains, and heating the resultant at a temperature of 60 to 110° C. to convert the crystal form of the resultant into B-type crystal.
 9. The method of claim 8, wherein the resulting B-type crystals of nateglinide are crystals wherein H-type crystals are not detected with DSC. 